A novel GIP analogue, ZP4165, enhances glucagon-like peptide-1-induced body weight loss and improves glycaemic control in rodents.

AIM: To investigate the effects of the novel glucose-dependent insulinotropic polypeptide (GIP) analogue, ZP4165, on body weight and glycaemic control in rodents, and to investigate if ZP4165 modulates the anti-obesity and anti-hyperglycaemic effects of a glucagon-like peptide-1 (GLP-1) agonist (liraglutide). METHODS: The acute insulinotropic effect of ZP4165 was investigated in rats during an oral glucose tolerance test. The long-term effects of ZP4165 on body weight and glycaemic control, either alone or in combination with liraglutide, were assessed in diet-induced obese mice and diabetic db/db mice. RESULTS: ZP4165 showed insulinotropic action in rats. The GIP analogue did not alter the body weight of obese mice but enhanced GLP-1-induced weight loss. In diabetic mice, 4 weeks' dosing with ZP4165 reduced glycated haemoglobin levels vs vehicle by an extent similar to the GLP-1 agonist. CONCLUSIONS: ZP4165 potentiated the anti-obesity effect of a GLP-1 agonist in obese mice and improved glycaemic control in diabetic mice. These studies support further investigation of dual-incretin therapy as a more effective treatment option than mono GLP-1 medication for type 2 diabetes mellitus and obesity.

Modeling energy intake and body weight effects of a long-acting amylin analogue.

The inhibitory effect of anti-obesity drugs on energy intake (EI) is counter-acted by feedback regulation of the appetite control circuit leading to drug tolerance. This complicates the design and interpretation of EI studies in rodents that are used for anti-obesity drug development. Here, we investigated a synthetic long-acting analogue of the appetite-suppressing peptide hormone amylin (LAMY) in lean and diet-induced obese (DIO) rats. EI and body weight (BW) were measured daily and LAMY concentrations in plasma were assessed using defined time points following subcutaneous administration of the LAMY at different dosing regimens. Overall, 6 pharmacodynamic (PD) studies including a total of 173 rats were considered in this evaluation. Treatment caused a dose-dependent reduction in EI and BW, although multiple dosing indicated the development of tolerance over time. This behavior could be adequately described by a population model including homeostatic feedback of EI and a turnover model describing the relationship between EI and BW. The model was evaluated by testing its ability to predict BW loss in a toxicology study and was utilized to improve the understanding of dosing regimens for obesity therapy. As such, the model proved to be a valuable tool for the design and interpretation of rodent studies used in anti-obesity drug development.

Versatile flow-injection amperometric ion detector based on an interface between two immiscible electrolyte solutions: numerical and experimental characterization.

The present paper describes a flexible thin layer electrochemical flow cell for ultrasensitive amperometric detection at a supported interface between immiscible electrolyte solutions. Nanomolar detection limits were demonstrated using the cell design, and 3D finite element simulations allowed a detailed characterization of the flow cell. The cell design employed in the present work allowed the sensing oil membrane and the aqueous reference electrode to be placed in close contact, thereby minimizing cell resistance. The adjustable cell volume means that the same cell design can be used for different application with different requirement for detection limits and dynamic range. A disposable membrane was employed which reduces the need for surface cleaning and prevents sample carryover between different applications. For the lowest cell volumes the detection chamber approaches a thin layer electrochemical flow cell detector with a large surface to volume ratio.

Effect of alpha-cyclodextrin on drug distribution studied by electrochemistry at interfaces between immiscible electrolyte solutions.

The description and understanding of noncovalent interactions and distribution of potential new drug compounds in an organism is of paramount importance for the successful development of new drugs. In this work, a new procedure based on electrochemistry at the interface between two immiscible electrolyte solutions (ITIES) for addressing and discriminating between drug compound/ligand interactions in aqueous solution and nonspecific ligand effects on oil-water distribution behavior has been developed. The procedure is demonstrated using five drug compounds with different physical chemical parameters and alpha-cyclodextrin as the aqueous phase ligand. Alpha-cyclodextrin was chosen as an aqueous phase ligand, as it is frequently used in drug formulations to enhance solubility and bioavailability of drug compounds. Supplementary capillary electrophoresis experiments provided more detailed information on alpha-cyclodextrin drug complexation and, in combination with the electrochemical studies, provided information on solvation effects affecting the oil-water distribution of the drug compounds. The use of ligand shift ion partition diagrams for data presentation is a convenient format for the visualization of ligand effects on distribution behavior of related drug compounds.

Molecular interactions in lipophilic environments studied by electrochemistry at interfaces between immiscible electrolyte solutions.

The description and understanding of absorption and distribution of potential new drug compounds in the organism is of paramount importance for the successful development of new drugs. However, the currently used physical chemical parameters such as oil-water distribution coefficients and ionization constants frequently fall short when it comes to a detailed description of the highly heterogeneous environments of both lipophilic and hydrophilic characters through which the drug compound passes. In this work, a new procedure based on electrochemistry at the interface between immiscible electrolyte solutions for addressing drug compound-ligand interactions in lipophilic environments as well as nonspecific ligand effects on distribution behavior has been developed. An attractive feature of the method is that it can simultaneously provide data for oil-water partition coefficients and ionization constants. The new procedure is demonstrated using five drug compounds with different physical chemical parameters and cholesterol as the oil-phase ligand. The use of ligand shift ion partition diagrams in the data presentation allows a quick visualization and comparison of a series of related drug compounds.